This invention relates to certain heterocyclic compounds and their use as sensitizers of tumor cells to anticancer agents and sensitizers of multidrug resistant forms of malaria (Plasmodium falciprum), tuberculosis, leishmania and amoebic dysentry. The compounds are also useful in facilitating delivery of cancer chemotherapeutants and other drugs across the blood-brain barrier, treatment of AIDS (especially in enhancing intracellular accumulation of drugs in infected lymphocytes) in humans and sensitization of multidrug resistant infections in humans and animals (especially Eimerian coccidial).
In cancer chemotherapy the effectiveness of anticancer drugs is often limited by the resistance of tumor cells. Some tumors such as of the colon, pancreas, kidney and liver are generally innately resistant, and other responding tumors often develop resistance during the course of chemotherapy. The phenomena of multidrug resistance (MDR) is typically characterized by the tumor cell's cross-resistance to adriamycin, daunomycin, vinblastine, topotecan, teniposide, vincristine, taxol, actinomycin D and etoposide. The resistance of cells is often associated with overexpression of the MDR1 gene. This gene encodes for a 140-220 kd trans-membrane phosphoglycoprotein (P-glycoprotein) which functions as an ATP-dependent efflux pump. Thus, it has been postulated that this efflux mechanism keeps the intracellular level of the anticancer drug low, allowing the tumor cells to survive.
In recent years various substances such as verapamil, nifedipine trifluoroperazine, and diltiazem have been used in in vitro experimental systems to reverse the MDR phenomena. More recently some of these agents have been tested clinically as MDR reversing agents. Little efficacy has been observed with verapamil or trifluoroperazine. Thus, there is a need for an effective MDR reversing agent.
Quinoline derivatives and other related compounds are claimed as anti-cancer drug reinforcing agents in European Patent Application 0 363 212.